Promising candidates for effective yet gentle drugs: Researchers have shown the potential of three herbal substances in the fight against the coronavirus. Their effect was shown in an X-ray screening of many natural substances at the German Electron Synchrotron DESY. The active ingredients found in olive oil, copper leaf and marigold block an important enzyme in the corona virus. They could thus form the basis for the development of new drugs, say the scientists.
The corona viruses and their various forms have proven to be stubborn opponents and therefore the search for new control strategies is still in full swing. In addition to the development of vaccines and antibodies, scientists are also exploring ways of intervening in the development processes of the virus. An important starting point is to prevent the pathogen from multiplying in affected cells. A promising target is a special enzyme: the so-called papain-like protease (Plpro). It has already been shown to serve as a kind of scissors for the virus to "tinker" with its offspring.
When the coronavirus hijacks a cell, it first forces it to produce building blocks for assembling new virus particles. However, these proteins are formed in the form of a long chain. This is why the pathogen also triggers the formation of its scissors: PLpro cuts the sequence into the individual protein building blocks, which then make up the virus particles. This in turn means that if the scissors are unusable, the pathogen cannot multiply. “PLpro also has another important function for the virus. It blocks an immune system protein called ISG15, and this severely weakens the cell's ability to defend itself. If we can block PLpro, we can also strengthen the cell's immune response," says Vasundara Srinivasan from the University of Hamburg.
Search for active ingredients among natural substances
Against this background, Srinivasan and her colleagues have now devoted themselves to the search for substances that interact with PLpro. In doing so, they specifically targeted well-known natural substances, as they have often become the basis for the development of drugs to treat numerous diseases. "For our study, we tested 500 substances from the Karachi Library of Natural Compounds to see whether they bind to the papain-like protease of the novel coronavirus. Because an active ingredient that attaches itself to the enzyme in the right place can block its function,” explains Srinivasan.
For the screening, PLpro was mixed with each of the 500 natural test substances, so that possible reactions could occur. However, it is not possible to determine with conventional test methods whether a binding to the enzyme occurs. However, this is possible through so-called X-ray screening at the German Electron Synchrotron DESY. To do this, Srinivasan and her colleagues grew tiny crystals from the 500 test mixtures. These crumbs were then exposed to the special X-ray light of the "PETRA III" facility. As the team explains, the crystals in it produce a characteristic diffraction pattern that allows conclusions to be drawn about the structure of the enzyme down to the level of individual atoms. "From this information we can create three-dimensional models of the enzyme with atomic resolution and see if and where a substance binds to the enzyme," says co-author Alke Meents from DESY.
Three candidates from Marigold and Co
As the researchers report, the screening revealed that three of the substances examined actually bind to PLpro. These are substances from the group of phenols: Hydroxyethylphenol (YRL) is a compound that is found in many foods such as red wine and olive oil and is already used as a remedy for cardiac arrhythmias. The second active ingredient is hydroxybenzaldehyde (HBA), which the plant Acalypha torta (copper leaf) forms and which is already used as an antitumor agent and for wound healing. Number three is methyl dihydroxybenzoate (HE9) isolated from the tagetes patula. It is known as an antioxidant with anti-inflammatory effects and is also found in green tea.
Subsequent investigations enabled the researchers to further underscore the potential of the three substances: In laboratory tests, the three phenols slowed down the activity of PLpro in living cells by 50 to 70 percent. However, the team emphasizes that the natural carriers of the substances are not suitable as home remedies against corona - the active ingredient levels are too low for that. "Drinking green tea will not cure a corona infection! Just as it would not heal wounds or cancer,” says co-author Christian Betzel from the University of Hamburg. Nevertheless, the naturalness and already established use is an important aspect: "The advantage of these substances is their proven safety. Whether and how a corona agent can be developed based on these phenols is now being investigated further," says Betzel.
Source: German Electron Synchrotron DESY, technical article: Communications Biology, doi: 10.1038/s42003-022-03737-7